Mechanical performance, intracellular Ca²⁺ handling and ventricular repolarisation in isolated hearts from rabbits with heart failure
In this thesis, a rabbit coronary artery ligation model was used to study the cardiac mechanical performance, Ca2+ handling and ventricular activation/repolarisation in heart failure. Significant cardiac dilatation and contractile dysfunction were demonstrated in vivo on echocardiography 7 weeks after the initial myocardial infarct resulting from the coronary artery ligation procedure. In addition, liver, lung and heart weights were increased indicating significant organ congestion, cardiac remodelling and hypertrophy as seen in the human clinical syndrome of heart failure. Impaired mechanical performance was also demonstrated in vitro in the isolated failing hearts both in the working heart configuration and during Langendorff perfusion, with significant systolic and diastolic dysfunction. The Frank-Starling relationship was attenuated in the failing hearts and there was also a blunted slow response to step increase in pre-load, which may partly explain the findings of the Frank-Starling relationship in the failing hearts. Epicardial Ca2+ transients measured from the isolated failing hearts were found to have a prolonged time course. Impaired relaxation was shown to be associated with the prolonged Ca2+ transient durations in the failing hearts and there was an increased variation of Ca2+ transient durations over the left ventricular epicardial surface in the failing hearts. Monophasic Action Potentials (MAPs) measured from the left ventricular epicardial surface of failing hearts also had a prolonged time course and there was also an increased variation of MAP durations. The prolonged Ca2+ transient durations appeared to be associated with prolonged MAP durations in the failing hearts. Finally, delayed ventricular activation with impaired intraventricular conduction was demonstrated in the failing hearts, which may be an additional contributory factor in the mechanical dysfunction in heart failure.